Bioavailabilty and pharmacokinetics of four active alkaloids of traditional Chinese medicine Yanhuanglian in rats following intravenous and oral administration
Introduction
Hepatitis B virus (HBV) is known to cause acute hepatitis, chronic hepatitis, fulminant hepatitis, and has been linked to hepatocelluar carcinoma (HCC). Treatment of chronic hepatitis B with interferon, antiviral agents and immunomodulatory drugs has been employed, either alone or in combination. However, there is still an urgent need to search for even more effective drugs.
In China, and other Asian countries, the use of medicinal plants is commonplace for the treatment of hepatic disease such as hepatitis. Among these plants, Corydalis saxicola Bunting (Yanhuanglian) is used. Yanhuanglian grows in south China and is an important component in various prescriptions in traditional Chinese medicine. Yanhuanglian has been demonstrated to possess many pharmacological activities, including antibacterial, antiviral and anticancer activities. Clinically, Yanhuanglian has been reported to protect hepatic tissues from hepatitis B virus and hepatitis A viral damage. Moreover, Yanhuanglian can also be used for alleviating fever, detoxification and as a painkiller [1], [2], [3], [4], [5].
The isolation and purification of the methanol extract afforded mainly four alkaloids of quaternary ammonium protoberberine type: dehydrocavidine, coptisine, dehydroapocavidine and tetradehydroscoulerine, which are named as YHL-I, YHL-II, YHL-III and YHL-IV (for chemical structures see Fig. 1), respectively. In addition, further studies showed that the active fraction contained 40% YHL-I, 15% YHL-II, 40% YHL-III and 5% YHL-IV by HPLC-UV analysis.
There is merit in characterizing the pharmacokinetics of four active alkaloids from Yanhuanglian extract in animals, since to our knowledge there was no detailed pharmacokinetic profiles for simultaneous characterization of these alkaloids. Recently, we have developed an HPLC coupled with tandem mass spectrometry method for simultaneously quantitating the four active alkaloids in plasma and urine [6]. By using this method, we evaluated in detail the in vivo pharmacokinetics, bioavailability and excretion via urine in rats following intravenous and oral administration.
Section snippets
Plant material
The herb of C. saxicola was collected in Jinchengjiang, Guangxi Province, PR China, in July of 2003, and authenticated by Prof. Hanchen Zheng, Department of Pharmacognosy, Second Military Medical University. The voucher specimens (collection No. 188) are deposited at Herbarium of School of Pharmacy, Second Military Medical University, Shanghai, China.
Preparation of the total alkaloids
The dried and powdered herb of C. saxicola (1 kg) was extracted with 20 L ethanol by infiltration. The solvent was evaporated under vacuum to afford
Pharmacokinetics of YHL-I, II, III, IV in rats following intravenous administration
Following intravenous administration, plasma drug concentration–time profiles can be best described as a two compartmental model (Fig. 2A). The pharmacokinetic parameter values are summarized in Table 1. YHL-I, II, III, IV were quickly eliminated with systemic clearance of 0.10 ± 0.02, 0.08 ± 0.03, 0.06 ± 0.01, and 0.05 ± 0.01 l/min/kg, which is about 180%, 147%, 111% and 93% of hepatic blood flow (0.055 l/min/kg in rats) [15], suggesting that those four active alkaloids were quickly cleared via hepatic
Conclusions
Systemic clearance of the four active alkaloids in plasma was over 93% of hepatic blood flow, indicating that they may be quickly eliminated via hepatic clearance. Less than 10% of the drugs was excreted via urine following intravenous and oral administration. This result demonstrated that these four alkaloids may undergo significant metabolism in the body or the drug may be excreted via routes other than urine. The results were supported by higher hepatic clearance for these four alkaloids.
Acknowledgement
The work was supported in part by the Scientific Foundation of Shanghai China (Nos. 03QMH1414, 04DZ19843, 04DZ19856, 04DZ19857 and 04DZ19842).
References (15)
- et al.
J. Chromatogr. B
(2006) - et al.
Zhiwu Xuebao
(1982) - et al.
Mianyixue Zazhi
(1995) - et al.
Acta Pharm. Sinica
(1981) Zhongyao Tongbao
(1982)- et al.
Shenyang Yaoxueyuan Xuebao
(1994) - et al.
J. Liq. Chromatogr.
(2005)
Cited by (31)
Dehydrocavidine attenuates D-galactose induced learning and memory impairment in rats
2018, Neuroscience LettersCitation Excerpt :Corydalis saxicola Bunting (Yanhuanglian) is a plant in TCM to treat hepatitis and liver cirrhosis [10]. The major component is DEH with hepatic protection effects, including killing hepatitis viruses, promoting regeneration of hepatocytes, possessing antioxidant activities [7,8,11]. In the current study, we reported DEH could attenuated d-gala induced learning and memory impairment in rats.
Antitumor lignanamides from the aerial parts of Corydalis saxicola
2016, PhytomedicineCitation Excerpt :Chinese name Yanhuanglian), which belongs to the Papaveraceae family, is a perennial herb that is mainly distributed in southwest China (Wang et al., 2009). Extracts of this plant and its constituents have been reported to possess antibacterial, antiviral, and antitumor activities (Li et al., 2006, 2008; An and Wang, 2014). Previous phytochemical investigations of C. saxicola have focused on isoquinoline alkaloids with activities against anti-hepatitis B virus and inhibition of DNA topoisomerase I (Cheng et al., 2008; Li et al., 2008; Zeng et al., 2013).
LC-MS/MS determination and urinary excretion study of seven alkaloids in healthy Chinese volunteers after oral administration of Shuanghua Baihe tablets
2016, Journal of Pharmaceutical and Biomedical AnalysisCitation Excerpt :In this study, the seven active alkaloids, magnoflorine, berberrubine, jatrorrhizine, coptisine, epiberberine, palmatine and berberine, were chosen as the representative components to evaluate their urinary excretion in human. Although studies on urinary excretion profiles of the classical alkaloids such as berberine, palmatine, jatrorrhizine and coptisine have been reported, they were mainly limited to animal experiments [12–16], and few studies focused on magnoflorine and berberrubine. The methods [17–20] for the quantitation of jatrorrhizine, coptisine, epiberberine, palmatine and berberine in traditional Chinese medicine were reported.
Alkaloids: An overview of their antibacterial, antibiotic-enhancing and antivirulence activities
2014, International Journal of Antimicrobial AgentsCitation Excerpt :Studies describing naturally occurring antibacterial alkaloids date back to the 1940s, but much of this early work stopped short of determining minimum inhibitory concentrations (MICs). Subsequent research has been more thorough, and several potently antibacterial alkaloid monomers (MICs ≤10 μg/mL) have been identified in the aaptamine [46], indole [47–52], indolizidine [53], isoquinoline [54–59], piperazine [60], quinoline [61,62], quinolone [63], agelasine [64,65] and polyamine [32] classes. Alkaloid dimers with similar levels of activity have been found in the aaptamine-indole [66], bisindole [67,68], indole-quinoline [69,70], pyridoacridine [71,72], bispyrrole [73–75] and pyrrole-imidazole [76] classes.
Comparative analysis of quinolizidine alkaloids from different parts of Sophora alopecuroides seeds by UPLC-MS/MS
2012, Journal of Pharmaceutical and Biomedical AnalysisCitation Excerpt :In addition, these HPLC methods will take a long analytical time. Recent success in the use of liquid chromatography coupled with triple quadrupole mass spectrometry (LC–MS/MS) for characterizing and quantifying a wide variety of compounds in complex samples [17–19] suggests that LC–MS/MS might be a technique in the determination of multiple quinolizidine alkaloids in complex plant extracts. Ultra-high-performance liquid chromatography coupled with a triple quadrupole electrospray tandem mass spectrometry (UPLC–MS/MS) is a powerful tool to solve the problems of above methods because of its high sensitivity and rapid resolution.
Hepatoprotective effects and mechanisms of dehydrocavidine in rats with carbon tetrachloride-induced hepatic fibrosis
2011, Journal of EthnopharmacologyCitation Excerpt :The mechanisms underlying hepatic protection of Yanhuanglian is not completely understood yet. HPLC–UV analysis showed Corydalis saxicola Bunting contains 40% (w/w) dehydrocavidine (DC), 15% coptisine (w/w), 40% dehydroapocavidine (w/w), and 5% tetradehydroscoulerine (w/w) (Li et al., 2006). Previous studies have shown that DC, a main ingredient of Corydalis saxicola Bunting, exhibits antinociceptive and spasmolytic activities (Bhakuni and Chaturvedi, 1983; Huo et al., 2007).